Field of the Invention
This invention relates to novel pentacyclic pyridoindolobenz[b,e]azepine derivatives for the treatment of neurological disorders.
Description of the Related Art
Various prior art references in the specification are indicated by italicized Arabic numerals in brackets. Full citation corresponding to each reference number is listed at the end of the specification, and is herein incorporated by reference in its entirety in order to describe fully and clearly the state of the art to which this invention pertains.
Unless otherwise specified, all technical terms and phrases used herein conform to standard organic and medicinal chemistry nomenclature established by International Union of Pure and Applied Chemistry (IUPAC), the American Chemical Society (ACS), and other international professional societies. The rules of nomenclature are described in various publications, including, “Nomenclature of Organic Compounds,” [1], and “Systematic Nomenclature of Organic Chemistry” [2], which are herein incorporated by reference in their entireties.
Neurological disorders comprise several major diseases as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-R) [3]. It is well-established that a particular neurological disorder may involve complex interactions of multiple neuroreceptors and neurotransmitters, and, conversely, a single neuroreceptor may be implicated in several disorders, both neurological and non-neurological. For example, the serotonin receptor is implicated in numerous disorders such as depression, anxiety, pain (both acute and chronic), etc.; the dopamine receptor is implicated in movement disorder, addiction, autism, etc; and the sigma receptors are involved in pain (both acute and chronic), and cancer. Many of the receptors that are found in the brain are also found in other areas of the body, including gastrointestinal (GI) tract, blood vessels, and muscles, and elicit physiological response upon activation by the ligands.
The rational drug design process is based on the well-established fundamental principle that receptors, antibodies, and enzymes are multispecific, i.e., topologically similar molecules will have similar binding affinity to these biomolecules, and, therefore, are expected to elicit similar physiological response as those of native ligands, antigens, or substrates respectively. Although this principle, as well as molecular modeling and quantitative structure activity relationship studies (QSAR), is quite useful for designing molecular scaffolds that target receptors in a “broad sense,” they do not provide sufficient guidance for targeting specific receptor subtypes, wherein subtle changes in molecular topology could have substantial impact on receptor binding profile. Moreover, this principle is inadequate for predicting in vivo properties of any compound; hence, each class of compound needs to be evaluated in its own right for receptor subtype affinity and selectivity, and in in vivo models to establish efficacy and toxicity profiles. Thus, there is a sustained need for the discovery and development of new drugs that target neuroreceptor subtypes with high affinity and selectivity in order to improve efficacy and/or minimize undesirable side effects.
Serotonin and sigma receptors are widely distributed throughout the body. To date, fourteen serotonin and two sigma receptor subtypes have been isolated, cloned, and expressed. Serotonin receptors mediate both excitatory and inhibitory neurotransmission, and also modulate the release of many neurotransmitters including dopamine, epinephrine, nor-epinephrine, GABA, glutamate and acetylcholine as well as many hormones such as oxytocin, vasopressin, corticotrophin, and substance P [4, 5]. During the past two decades, serotonin receptor subtype selective compounds have been a rich source of several FDA-approved CNS drugs. Most of these serotonin receptor subtypes have been focus of research in the past couple of decades and this effort has led to the discovery of important therapeutics like Sumatriptan (5-HT1B/1D agonist) for the treatment of migraine, Ondansetron (5-HT3 agonist) for the treatment of radiation or chemotherapy-induced nausea and vomiting, and Zyprexa (5-HT2A/D2 antagonist) for the treatment of schizophrenia. Therapeutic targets have been identified for 5-HT4 (learning and memory) [6], 5-HT5A (cognition, sleep) [7], 5-HT6 (learning, memory) [8] and 5-HT7 (pain and depression) [9, 10], and some selective ligands have been prepared for all of these receptors with the exception of 5-HT5A. However, no CNS drug has yet emerged out of this effort. Thus, there is a need for selective high affinity agonists and antagonists that target serotonin and dopamine receptors for combating various CNS and peripheral disorders implicated by these neurotransmitter systems.
Among the various CNS disorders, drug addiction continues to be an important target for therapeutic intervention. Drug addiction is a devastating CNS disorder with enormous cost to the individual, family, and society. Presently, there is no cure for drug addiction, and overwhelming majority of patients (nearly 85%) undergoing modern day rehabilitation relapse back into compulsive drug consumption. Relapse is motivated by the intense craving for the drug that is experienced by the drug-withdrawn addict, even after being drug-free for many years. Methamphetamine (meth) (1) and 3,4-methylenedioxyamphetamine (MDMA) (2) are increasingly popular psychostimulant/hallucinogenic drugs with extremely high abuse
liabilities. MDMA, commonly known as ‘Ecstasy’ is one of the most extensively abused drugs worldwide during the past several years. It is a recreational drug very popular among the ‘rave’ users and is legally controlled in most countries of the world under UN Convention on Psychiatric Drugs and other international agreements. It is estimated that about 30% of the Americans between the ages of 16 and 25 have used MDMA at least once in their lifetime and majority of them have become habituated to it. The number of life-time users is about 11.6 million in 2009. The cost of treatment meth and MDMA addictions to the individual, society, and the government runs into millions of dollars in the United States alone and, therefore, the development of an effective medication for the treatment of psychostimulant abuse/addiction remains one of the top priorities of the National Institutes on Drug Abuse.
Progress achieved in this field shows the fundamental contribution of brain 5-HT1A and 5-HT2B receptors to virtually all behaviors associated with psychostimulant addiction. Recent data not only show a crucial role of 5-HT1A receptors in the control of brain 5-HT activity and spontaneous behavior, but also their complex role in the regulation of the psychostimulant-induced 5-HT response and subsequent addiction-related behaviors [10] such as comorbid depression. Likewise, Luc Maroteaux et al., reported that serotonin 5-HT2B receptor antagonists are required, and do play an important role in the modulation of serotonin release by MDMA in the brain [11]. These recent findings clearly suggest that 5-HT1A/2B receptor ligands would be useful for the treatment of psychostimulant abuses and comorbidity resulting therefrom.
Rajagopalan [12, 13] and Adams et al. [14] disclosed the pentacyclic scaffolds incorporating the γ-carboline pharmacophore 3-6, where the two phenyl rings are fused at the
‘b’ and ‘f’ positions in the 7-membered D-ring. In particular, the sulfur analog 6b has been shown recently to have atypical antipsychotic properties [15]. However, other pentacyclic analogs, where the E-phenyl ring being fused at other positions in the 7-membered D-ring, have not been disclosed.